Simvastatin Enhances the Effects of Radiotherapy and Cetuximab on a Cell Line (FaDu) Derived from a Squamous Cell Carcinoma of Head and Neck

Abstract

Radiotherapy (XRT) delivered with the antibody cetuximab is a standard treatment option for squamous cell carcinomas of head and neck (SCCNH). Cetuximab acts by blocking epidermal growth factor receptor (EGFR) signaling to inhibit cancer progression. However, a significant percentage of patients will not respond to XRT and cetuximab. Statins reduce the synthesis of cholesterol and isoprenoid derivates that may be required for efficient EGFR signaling. We assessed whether the statin simvastatin could improve this combined therapy. In vitro, simvastatin enhanced the effects of XRT alone and in combination with cetuximab in wound healing, cell proliferation, and clonogenic assays in FaDu cells. These results were reflected in xenoimplanted tumors growing into subcutaneous tissue of athymic mice where concomitant treatment with simvastatin decreased tumor growth. Consistently, lower levels of phosphorylated extracellular signal–regulated kinases 1 and 2, phosphatidylinositol 3-kinase/AKT–protein kinase B, and signal transducer and activator of transcription 3 oncoproteins and higher levels of caspase-3 and apoptosis in cell cultures and xenografts were observed. The EGFR-overexpressing A431 cell line was used to reproduce these antitumor effects of simvastatin. Our findings suggest that simvastatin may improve the efficiency of concomitant XRT and cetuximab. Further investigation in the treatment of SCCNH is warranted.

In vitro Anti-Tumor Effects of Statins on Head and Neck Squamous Cell Carcinoma: A Systematic Review

“…The studies were published from 2001 to 2014, and all of them were in English. They were conducted in five different countries: Canada [ 6 , 8 , 9 , 11 , 20 – 23 ], France [ 24 ], Germany [ 25 ], Spain [ 26 ] and the United States of America [ 7 , 27 , 28 ]. All of the selected studies were in vitro [ 6 – 9 , 11 , 20 – 27 ]; however, three of them also involved in vivo experiments [ 7 , 25 , 26 ].…”

“…We used the GRADE method [ 18 ] to assess the quality of the studies. Six studies were categorized as moderate quality [ 7 , 9 , 20 , 24 , 26 , 28 ]. One of these [ 20 ] did not show results in all the tested cell lines, so the study could not answer all of our questions.…”

“…The articles published by Pioche-Durieu et al [ 24 ] in 2005 and by Islam et al [ 7 ] in 2013 did not completely pertain to the review questions defined in this systematic review; therefore, we considered their usefulness to this work limited. Specifically, the article by Pioche-Durieu et al [ 24 ] did not quantify cell viability, and the papers by Islam et al [ 7 ] and Llobet, et al [ 26 ] did not test cell viability, although they did show that statins regulated the expression of signal transducer and activator of transcription 3 (STAT3) and ERK 1/2 extracellular signal-regulated kinases (ERK 1/2) in HNSCCs. Lastly, the 2011 paper by Wang et al [ 28 ] tested only one cell line and did not compare the results to another cell line ( Table 3 ).…”

Efeitos in vitro das estatinas em câncer de cabeça e pescoço

“…The studies were published from 2001 to 2014, and all of them were in English. They were conducted in five different countries: Canada [6,8,9,11,[20][21][22][23], France [24], Germany [25], Spain [26] and the United States of America [7,27,28]. All of the selected studies were in vitro [6-9, 11, 20-27]; however, three of them also involved in vivo experiments [7,25,26].…”

“…The articles published by Pioche-Durieu et al [24] in 2005 and by Islam et al [7] in 2013 did not completely pertain to the review questions defined in this systematic review; therefore, we considered their usefulness to this work limited. Specifically, the article by Pioche-Durieu et al [24] did not quantify cell viability, and the papers by Islam et al [7] and Llobet, et al [26] did not test cell viability, although they did show that statins regulated the expression of signal transducer and activator of transcription 3 (STAT3) and ERK 1/2 extracellular signal-regulated kinases (ERK 1/2) in HNSCCs. Lastly, the 2011 paper by Wang et al [28] tested only one cell line and did not compare the results to another cell line (Table 3).…”